Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors

Abstract Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2 , resulted in the discovery of the more potent pyridofuran analogue 5 . Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41 , from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC 50 ) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC 50 ) was low.